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Ablation of EIF5A2 induces tumor vasculature remodeling and improves tumor response to chemotherapy via regulation of matrix metalloproteinase 2 expression.

Wang FW, Cai MY, Mai SJ, Chen JW, Bai HY, Li Y, Liao YJ, Li CP, Tian XP, Kung HF, Guan XY, Xie D - Oncotarget (2014)

Bottom Line: In this study, EIF5A2 was identified to be an independent risk factor for poor disease-specific survival among HCC patients.Additionally, we found that ablation of EIF5A2 enhanced the chemosensitivity of HCC cells to 5-Fluorouracil (5-FU).Finally, we demonstrated that EIF5A2 might exert these functions by enhancing MMP-2 activity via activation of p38 MAPK and JNK/c-Jun pathways.

View Article: PubMed Central - PubMed

Affiliation: State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine; Sun Yat-sen University Cancer Center, Guangzhou, China. These authors contributed equally to this work.

ABSTRACT

Unlabelled: Hepatocellular carcinoma (HCC) is a highly vascularized tumor with poor clinical outcome. Our previous work has shown that eukaryotic initiation factor 5A2 (EIF5A2) over-expression enhances HCC cell metastasis. In this study, EIF5A2 was identified to be an independent risk factor for poor disease-specific survival among HCC patients. Both in vitro and in vivo assays indicated that ablation of endogenous EIF5A2 inhibited tumor angiogenesis by reducing matrix metalloproteinase 2 (MMP-2) expression. Given that MMP-2 degrades collagen IV, a main component of the vascular basement membrane (BM), we subsequently investigated the effect of EIF5A2 on tumor vasculature remodeling using complementary approaches, including fluorescent immunostaining, transmission electron microscopy, tumor perfusion assays and tumor hypoxia assays. Taken together, our results indicate that EIF5A2 silencing increases tumor vessel wall continuity, increases blood perfusion and improves tumor oxygenation. Additionally, we found that ablation of EIF5A2 enhanced the chemosensitivity of HCC cells to 5-Fluorouracil (5-FU). Finally, we demonstrated that EIF5A2 might exert these functions by enhancing MMP-2 activity via activation of p38 MAPK and JNK/c-Jun pathways.

Conclusion: This study highlights an important role of EIF5A2 in HCC tumor vessel remodeling and indicates that EIF5A2 represents a potential therapeutic target in the treatment of HCC.

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Related in: MedlinePlus

Association among expression of EIF5A2, MMP-2, MVD and its prognostic significance in HCC patients(A) Representative images of IHC staining for EIF5A2, MMP-2 and CD34 in two HCC cases (100x). EIF5A2 expression positively correlated with MMP-2 expression and tumor MVD. (B) X-tile analysis was employed to determine the cut-point for EIF5A2 expression in HCC. The cut-point (H score=150) highlighted by the black/white circle in the horizontal axis (left panel) was demonstrated on a histogram of the cohort (middle panel), and a Kaplan-Meier plot (right panel).
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Figure 3: Association among expression of EIF5A2, MMP-2, MVD and its prognostic significance in HCC patients(A) Representative images of IHC staining for EIF5A2, MMP-2 and CD34 in two HCC cases (100x). EIF5A2 expression positively correlated with MMP-2 expression and tumor MVD. (B) X-tile analysis was employed to determine the cut-point for EIF5A2 expression in HCC. The cut-point (H score=150) highlighted by the black/white circle in the horizontal axis (left panel) was demonstrated on a histogram of the cohort (middle panel), and a Kaplan-Meier plot (right panel).

Mentions: Immunoreactivity for EIF5A2 was examined primarily in the cytoplasm of tumor cells. The nuclear expression of EIF5A2 was also observed in 36 (36/212) HCC cases. The association between EIF5A2 expression and either MMP2 expression or angiogenesis in 212 HCC patients were further assessed using immunohistochemistry on a tissue micro-array (TMA) platform, which demonstrated that EIF5A2 expression was significantly associated with MMP-2 expression as well as MVD (P=0.022 and P=0.030) (Table. 1 and Fig. 3A). Based on the X-tile analysis, the cut-point for high expression of EIF5A2 was defined when the H scores were above 150. Further correlation analysis showed that EIF5A2 over-expression in HCCs was significantly associated with tumor multiplicity and stage (P<0.05, Table 1). Kaplan–Meier analysis established that patients with high EIF5A2 expression had poorer disease-specific survival compared to those with low EIF5A2 expression (Log-rank test, P<0.001) (Table 2 and Fig. 3B). Multivariate Cox regression analysis identified EIF5A2 expression as an independent risk factor for poor disease-specific survival of HCC patients, with a hazard ratio (HR) of 1.522 (95% confidence interval [CI]: 1.065-2.175) (P=0.021) (Table 3). Moreover, transwell assay indicated that MMP2 was also involved in the inducible effect of EIF5A2 on tumor invasion (Supplementary Fig. 2). Taken together, these findings suggest that EIF5A2 overexpression may promote angiogenesis and invasion of HCC by enhancing MMP2 activity.


Ablation of EIF5A2 induces tumor vasculature remodeling and improves tumor response to chemotherapy via regulation of matrix metalloproteinase 2 expression.

Wang FW, Cai MY, Mai SJ, Chen JW, Bai HY, Li Y, Liao YJ, Li CP, Tian XP, Kung HF, Guan XY, Xie D - Oncotarget (2014)

Association among expression of EIF5A2, MMP-2, MVD and its prognostic significance in HCC patients(A) Representative images of IHC staining for EIF5A2, MMP-2 and CD34 in two HCC cases (100x). EIF5A2 expression positively correlated with MMP-2 expression and tumor MVD. (B) X-tile analysis was employed to determine the cut-point for EIF5A2 expression in HCC. The cut-point (H score=150) highlighted by the black/white circle in the horizontal axis (left panel) was demonstrated on a histogram of the cohort (middle panel), and a Kaplan-Meier plot (right panel).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4196158&req=5

Figure 3: Association among expression of EIF5A2, MMP-2, MVD and its prognostic significance in HCC patients(A) Representative images of IHC staining for EIF5A2, MMP-2 and CD34 in two HCC cases (100x). EIF5A2 expression positively correlated with MMP-2 expression and tumor MVD. (B) X-tile analysis was employed to determine the cut-point for EIF5A2 expression in HCC. The cut-point (H score=150) highlighted by the black/white circle in the horizontal axis (left panel) was demonstrated on a histogram of the cohort (middle panel), and a Kaplan-Meier plot (right panel).
Mentions: Immunoreactivity for EIF5A2 was examined primarily in the cytoplasm of tumor cells. The nuclear expression of EIF5A2 was also observed in 36 (36/212) HCC cases. The association between EIF5A2 expression and either MMP2 expression or angiogenesis in 212 HCC patients were further assessed using immunohistochemistry on a tissue micro-array (TMA) platform, which demonstrated that EIF5A2 expression was significantly associated with MMP-2 expression as well as MVD (P=0.022 and P=0.030) (Table. 1 and Fig. 3A). Based on the X-tile analysis, the cut-point for high expression of EIF5A2 was defined when the H scores were above 150. Further correlation analysis showed that EIF5A2 over-expression in HCCs was significantly associated with tumor multiplicity and stage (P<0.05, Table 1). Kaplan–Meier analysis established that patients with high EIF5A2 expression had poorer disease-specific survival compared to those with low EIF5A2 expression (Log-rank test, P<0.001) (Table 2 and Fig. 3B). Multivariate Cox regression analysis identified EIF5A2 expression as an independent risk factor for poor disease-specific survival of HCC patients, with a hazard ratio (HR) of 1.522 (95% confidence interval [CI]: 1.065-2.175) (P=0.021) (Table 3). Moreover, transwell assay indicated that MMP2 was also involved in the inducible effect of EIF5A2 on tumor invasion (Supplementary Fig. 2). Taken together, these findings suggest that EIF5A2 overexpression may promote angiogenesis and invasion of HCC by enhancing MMP2 activity.

Bottom Line: In this study, EIF5A2 was identified to be an independent risk factor for poor disease-specific survival among HCC patients.Additionally, we found that ablation of EIF5A2 enhanced the chemosensitivity of HCC cells to 5-Fluorouracil (5-FU).Finally, we demonstrated that EIF5A2 might exert these functions by enhancing MMP-2 activity via activation of p38 MAPK and JNK/c-Jun pathways.

View Article: PubMed Central - PubMed

Affiliation: State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine; Sun Yat-sen University Cancer Center, Guangzhou, China. These authors contributed equally to this work.

ABSTRACT

Unlabelled: Hepatocellular carcinoma (HCC) is a highly vascularized tumor with poor clinical outcome. Our previous work has shown that eukaryotic initiation factor 5A2 (EIF5A2) over-expression enhances HCC cell metastasis. In this study, EIF5A2 was identified to be an independent risk factor for poor disease-specific survival among HCC patients. Both in vitro and in vivo assays indicated that ablation of endogenous EIF5A2 inhibited tumor angiogenesis by reducing matrix metalloproteinase 2 (MMP-2) expression. Given that MMP-2 degrades collagen IV, a main component of the vascular basement membrane (BM), we subsequently investigated the effect of EIF5A2 on tumor vasculature remodeling using complementary approaches, including fluorescent immunostaining, transmission electron microscopy, tumor perfusion assays and tumor hypoxia assays. Taken together, our results indicate that EIF5A2 silencing increases tumor vessel wall continuity, increases blood perfusion and improves tumor oxygenation. Additionally, we found that ablation of EIF5A2 enhanced the chemosensitivity of HCC cells to 5-Fluorouracil (5-FU). Finally, we demonstrated that EIF5A2 might exert these functions by enhancing MMP-2 activity via activation of p38 MAPK and JNK/c-Jun pathways.

Conclusion: This study highlights an important role of EIF5A2 in HCC tumor vessel remodeling and indicates that EIF5A2 represents a potential therapeutic target in the treatment of HCC.

Show MeSH
Related in: MedlinePlus